Mutations in WDR34 is a rare cause of non-syndromic autosomal recessive rod-cone dystrophy

Abstract

Purpose : To identify the underlying gene defect in a patient with non-syndromic rod-cone dystrophy (RCD).

Methods : A 27-year old patient, of Portuguese descent and consanguineous union, with a presumed diagnosis of sporadic RCD was included in the study after informed consent. The DNA of the index patient was initially investigated applying microarray analysis, and direct Sanger sequencing of EYS and PCARE. Homozygosity mapping using a 700K genome-wide SNP microarray (Illumina HumanOmniExpress) was subsequently performed followed by Sanger sequencing of exonic regions known to be mutated in retinal dystrophies within homozygous regions. Whole exome sequencing (WES) was subsequently applied to the DNA of the index patient and his unaffected parents followed by segregation analysis in all available family members using Sanger sequencing. Further Sanger sequencing of the 9 exons and flanking regions of WDR34 (Refseq NM_052844.3) was performed on 1285 presumed autosomal recessive and sporadic cases with non syndromic RCD. The expression of WDR34 was investigated in transcriptomic databases and by RT-PCR and in situ hybridization experiments.

Results : Ophthalmic examination confirmed the diagnosis of RCD with macular involvement in the patient. There was no evidence of additional systemic abnormalities excluding a syndromic involvement. Microarray analysis and direct targeted sequencing did not identify disease causing variant. Homozygosity mapping identified 21homozygous regions ranging from 9kb to 77.7Mb. Subsequent whole exome sequencing identified a total 69552 unique variants with a global coverage of 95%. After stringent filtering for rare variants with predicted high functional impact, two variants were retained including the c.1241A>G change leading to p.(Asp414Gly) substitution in WDR34 which lies in a large homozygous region and co-segregated with the phenotype in the family. Mutation screening of additional 1285 presumed autosomal recessive non-syndromic RCD cases did not reveal any other likely pathogenic changes in WDR34.

Conclusions : This is the first report of a homozygous variant in WDR34 in a retina-restricted disease. Further functional studies will help better define phenotype/genotype correlations associated with WDR34 mutations leading either to severe syndromic ciliopathies or to non syndromic RCD, the latter appearing to be a rare occurrence.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.